tbuckley/cabot-search huggingface dataset:
Abstract 2608: Defining the function of tumor suppressor p53 arginine 181 residue in tumorigenesis
Authors: Renyta Moses, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, Kara Maxwell
Journal: Cancer Research (2023)

Abstract The gene Tp53 encodes for the protein p53 which has many tumor suppressive functions. Li-Fraumeni syndrome is characterized by germline Tp53 mutations that significantly increase the risk of cancer. The p53 amino acid residue arginine 181 is one such mutation site that promotes tumorigenesis by impacting a phenomenon known as p53 cooperativity. This is the ability of one p53 molecule to interact with another in order to efficiently bind specific sites on DNA to enact specific p53 functional pathways. Two p53 molecules interact with each other through the formation of a salt bridge between H1 helices found in respective DNA binding domains. The two key amino acid residues in this salt bridge are positively charged arginine (R) 181 and negatively charged glutamic acid (E) 180 which form electrostatic interactions with the residues on the opposite p53 H1 helix. Cooperativity mutants such as R181H and R181C show a hypomorphic behavior wherein much of p53’s canonical functions remain intact. Colony suppression data show that H1299 cells with p53 R181H and R181C yield a similar number of colonies as p53 wild type, which is significantly fewer than the yield of p53 hotspot mutation R175H and the absence of p53. Despite retaining some wild-type behavior, R181 mutants are found in LFS patients with cancer. Discovering the importance of the R181 residue for p53’s role in defending against tumorigenesis can lead to unique treatment opportunities for LFS patients with cooperativity mutants. Citation Format: Renyta Moses, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, Kara Maxwell. Defining the function of tumor suppressor p53 arginine 181 residue in tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2608.
Abstract 3282: Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder cancer
Authors: Kai-Jen Pai, I-Tsang Chiang, Fei-Ting Hsu, Jai-Jen Tsai
Journal: Cancer Research (2023)

Abstract Bladder cancer is one of the most common cancer in urinary system in Taiwan. According to Ministry of Health and Welfare’s research, bladder cancer plays 15th leading causes of death in Taiwan in 2020. Recently immune checkpoint inhibitor (ICI) therapy show several benefits on preventing T cell exhaustion, accumulating evidences showed ICI therapy still remain some limitation, including unable to regulated immunosuppressor cells and tumor microenvironment (TME) related elements which might lead to ICI therapy dysfunction. Recently, study report that DNA damage may activate the innate immune response and improve ICI efficacy. Thus, regulating DNA damage or illustrate the role of DNA damage related factor may bring the twilight to immunotherapy. To identify the possible combination methods with ICIs, we used MB49 cells and animal model to test the combination property of regorafenib (a multiple receptor tyrosine kinase inhibitor) and 10F.9G2 (a PD-L1 monoclonal antibody). Our research illustrated the mechanism between regorafenib and PD-L1, we proved that regorafenib-induced regulated PD-L1 is associated with ATM activation. TUENL assay showed regorafenib are able to activate ATM by causing DNA break and thus enhance the expression of PD-L1 on tumor surface. This effect could be an important step to open the interaction potential of PD-L1 antibodies and thus enhance its efficacy. Through the interaction analysis of miRNA targeting gene (RNA22), we found that IDO1 mRNA could specifically interact with endogenous miR-124. Here, the propose mechanism in our research is that regorafenib may downregulate IDO1 expression via increasing of endogenous miR-124 expression. In animal model, the combination therapy showed extraordinary therapeutic effect, not only dramatically decreased tumor volume, but also upregulating the positive TME components, such as CD8+T cells and M1 macrophage. Though regorafenib may induce PD-L1 expression, regorafenib still showed several therapeutic benefits, including downregulating immunosuppressive factors, such as IDO1, VEGF, and suppressing the accumulation of regulatory T cells, myeloid-derived suppressor cells and also repolarizing macrophage from M2-to-M1⋯etc. In conclusion, this study points out the combination therapy of regorafenib and anti-PD-L1 has present several benefits to bladder cancer patients and is associated with miR-124/ATM signaling. Citation Format: Kai-Jen Pai, I-Tsang Chiang, Fei-Ting Hsu, Jai-Jen Tsai. Regorafenib enhance PD-L1 expression via ATM activation and evaluate the therapeutic efficacy of combining PD-L1 antibody on bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3282.
Abstract 6560: Identification of distinct patterns in diffuse large B-cell lymphoma through alternative splicing analysis
Authors: Sanyeowool An, Youngil Koh, Sung-Soo Yoon
Journal: Cancer Research (2023)

Abstract Background Aberrant splicing in cancer cells contributes to cellular proliferation, escape from cell death, growth inhibition, invasion and metastasis, and immune escape. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, but the effect of AS on its pathogenesis has not been fully elucidated, so it is essential to find out DLBCL-specific splicing patterns and their potential as treatment targets. Material and Method RNA-Seq dataset from DLBCL patients was retrieved from The Cancer Genome Atlas (TCGA) DLBCL (N=48) and Pan-cancer Analysis of Whole Genomes (PCAWG) DLBC (N=7) were used as the cancer group. In order to identify spliced genes that are significantly different from normal tissue, RNA-Seq data of normal lymphoid tissue produced in two studies of E-MTAB-513 (N=1) and E-MTAB-1733 (N=13) from the BioStudies were downloaded. Sequence reads were aligned to the GRCh38 reference genome using STAR aligner. Results 5,470 genes identified as differentially spliced compared to normal in both rMATS and MAJIQ tools were studied. After sorting the AS events of these genes in order of highest average PSI value, events with an average PSI value of 0.7 or more in the top 2/3 samples and events with an average PSI value of 0.3 or less in the bottom 2/3 samples are selected. 8 exons of 7 genes were involved in Exon skipping (ES) events, 6 exons of 5 genes were involved in mutually exclusive exon (MXE) events, and an exon of a gene was involved in alternative 5' splice site (A5SS) Among these genes, exons 6 and 7 in CD53 showed high PSI values between exons 4 and 9. The average PSI values for exons 6 and 7 of CD53 in DLBCL were 0.923855 and 0.89096, respectively, which were significantly higher than the Normal group (p&amp;lt;0.05). CD53 mediates IL-7R signaling and plays a role in the regulation of normal B-cell development. As a gene coding for cell surface protein, it is involved in various immune systems in T-cell and B-cell surfaces. In healthy tissue, transcripts that skip exon 5 and have a junction between exon 4 and exon 6 or 7 are not yet known and should be further studied. In addition, SLAMF8, which has an exon with a PSI value specific to DLBCL, is also involved lymphocyte activation and regulates B-cell receptor signaling. Conclusion These DLBCL-specific patterns of selective exon usage are expected to be potential targets for cancer immunotherapy. Citation Format: Sanyeowool An, Youngil Koh, Sung-Soo Yoon. Identification of distinct patterns in diffuse large B-cell lymphoma through alternative splicing analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6560.
Abstract 2074: Genome Integrity assessment and verification by optical genome mapping for cell manufacturing/bioprocessing applications
Authors: Alex R. Hastie
Journal: Cancer Research (2023)

Abstract Cells and cell lines are used for multiple applications such as bioprocessing, therapy, and research. To ensure quality of cells and downstream applications, appropriate quality control (QC) methods are critical. Historically, karyotyping has been employed, but it is limited by its very low resolution and tedious laboratory workflow. Other methods such as PCR and targeted sequencing can characterize only small genomic variants at specific loci. Whole genome sequencing can detect small variants genome-wide but has limited sensitivity in detecting structural variants (SVs). Optical genome mapping (OGM) is a novel genome analysis technique that can fill many of the gaps in current capabilities for assessing genome integrity. To find clonal variants, 400 Gbp of data is collected from the parental/control and test samples. For both samples, a de novo assembly is constructed, and homozygous or heterozygous SVs are assessed. Subsequently, Bionano Access software’s dual variant annotation pipeline identifies unique SVs in the test sample compared to the parental sample. To discover subclonal SVs down to 5% variant allele fraction (VAF), the workflow leverages the generation of 1.5 Tbp of data, requiring a simple adjustment to longer data collection time. Comparison of test sample to parental sample easily enables the determination of acquired variants. Finally, generation of ~5 Tbp of data, requiring 2-3 flow cells to be run, enables the detection of SVs at ultra-low VAF down to ~1%. In this study, several dilutions and simulations were performed to examine OGM’s limit of detection. Targeting a coverage of 5 Tbp and analysis using the somatic SV-analysis workflow revealed that OGM has the sensitivity to detect deletions &amp;gt;50kbp, insertions &amp;gt;20kbp, duplications &amp;gt;100 kbp, and translocations at ~1% VAF. We have applied the clonal and somatic workflows to verify genomes’ integrity after cell immortalization, induced pluripotency, transgene-integration, and gene-editing. The data using the robust and sensitive workflows demonstrate that the OGM platform is a cost-effective solution for cell manufacturing/bioprocessing QC applications. Citation Format: Alex R. Hastie. Genome Integrity assessment and verification by optical genome mapping for cell manufacturing/bioprocessing applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2074.
Abstract 6798: CD8α+ dendritic cells potentiate the antitumor and immune activities against murine ovarian cancers
Authors: Shin-Wha Lee, Dasol Oh, Hyunah Lee, Kyung-Won Lee, Min-Je Kim, Sung Wan Kang, Young-Jae Lee, HyunSoo Kim, Yong-Man Kim
Journal: Cancer Research (2023)

Abstract Objectives: Dendritic cell (DC) based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. This study aimed to evaluate the effectiveness of mouse CD8α+ dendritic cells (DCs), corresponding to human CD141+ DCs, derived from bone marrow (BM) hematopoietic stem cells (HSCs) in a syngeneic and orthotopic mouse ovarian cancer model. Methods: Stem-DCs from HSCs and Mono-DCs from monocytes were generated from the bone marrow mononuclear cells (BM-MNCs) of C57BL/6 mice in condition of pulsing with ID8 tumor cell lysates. C57BL/6 mice were intraperitoneally injected with 5 × 106 ID8 cells. They were treated with vehicle, low/medium/high dose pulsed Stem-DCs, Mono-DCs, and unpulsed Stem-DCs. At 8 to 9 weeks, the treated mice were sacrificed, and tumor responses and immune responses, such as lymphocyte proliferation and cytokine secretion, were analyzed. Results: Mono-DCs and Stem-DCs were characterized by CD11c+CD80+CD86+ and CD8α+Clec9a+ expression, respectively. They were confirmed by the secretion of immunostimulatory cytokines, such as interleukin (IL)-12 and interferon (IFN)-γ, and T cell proliferation was observed after maturation. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle treated mice (P = 0.0021 and P = 0.0092, respectively). These mice treated with pulsed Stem-DCs appeared to have fewer tumor implants which were usually confined in the epithelium of ovaries, diaphragm and peritoneum. All mice injected with DCs demonstrated longer survival than the vehicle group (P = 0.0187), especially the medium/high dose pulsed Stem-DC treatment groups. Moreover, these favorable tumor responses were associated with a low proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, high IL-12 and IFN-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Conclusions: We demonstrated that mouse CD8α+ DCs derived from BM HSCs could decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs. Citation Format: Shin-Wha Lee, Dasol Oh, Hyunah Lee, Kyung-Won Lee, Min-Je Kim, Sung Wan Kang, Young-Jae Lee, HyunSoo Kim, Yong-Man Kim. CD8α+ dendritic cells potentiate the antitumor and immune activities against murine ovarian cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6798.
Abstract 766: A genome-wide association study identifies the association of common variants in the major histocompatibility complex with cervical cancer in black South African women
Authors: Abram Bunya Kamiza, Wenlong Carl Chen, Jean-Tristan Brandenberg, Michele Ramsay, Christopher G. Mathew
Journal: Cancer Research (2023)

Abstract Cervical cancer is the second most common female gynaecological malignancy in sub-Saharan Africa (SSA). Previous genome-wide association studies (GWASs) identified genetic variants associated with cervical cancer in women of European and Asian ancestry, particularly within the major histocompatibility complex (MHC). However, owing to the complexity of linkage disequilibrium and varied environmental exposures in different ancestral populations, regional GWASs are needed to investigate the genetic contribution to the pathogenesis of cervical cancer in continental African populations. A total of 1,637 cervical cancer patients and 761 controls in women of African ancestry were identified from the Johannesburg Cancer Study and the AWI-Gen study, respectively. DNA samples were genotyped on the 2.3 million H3Africa GWAS SNP array and genotyped SNPs imputed to a total of 13,937,308 SNPs. The association between genetic variants and cervical cancer was tested using linear mixed models, adjusting for five principal components and cryptic relatedness. We identified one locus within the MHC region associated with cervical cancer at genome-wide significance, led by rs3129965 (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.87-0.92, P = 2.292 x 10-11) near HLA-DRA. Four other loci were strongly associated with cervical cancer (P&amp;lt;5x10-7), including rs575105445 (OR=0.77, 95%CI=0.70-0.85, P = 2.188 x 10-07) near HLA-C,rs184053148 (OR =0.79, 95% CI = 0.72-0.86, P = 4.19 x 10-07) in TRIM31,rs12496921 (OR=0.88, 95%CI = 0.84-0.92, P = 1.32 x 10-07) in ROPN1B and rs114031308 (OR= 1.27, 95% CI =1.16-1.39, P =3.06 x 10-07) near TTC26. The genes in these loci are implicated in numerous pathways including antiviral immunity, DNA repair, the regulation of p53, apoptosis, cell growth and differentiation. These discoveries demonstrate the important contribution of common genetic variants to cervical cancer susceptibility and provide insights into its pathogenesis in women of African ancestry. Citation Format: Abram Bunya Kamiza, Wenlong Carl Chen, Jean-Tristan Brandenberg, Michele Ramsay, Christopher G. Mathew. A genome-wide association study identifies the association of common variants in the major histocompatibility complex with cervical cancer in black South African women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 766.
Q&amp;A: Robert Vonderheide on Immunotherapy Advances
Journal: Cancer Discovery (2023)

Researchers and oncologists have long looked to the body's own defenses as a possible tool to conquer cancer. To that end, they have developed checkpoint inhibitors, mRNA vaccines, chimeric antigen receptor T-cell therapies, and other treatments. Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, talks about where the field has been and what lies ahead.
Abstract 6553: The development of homologous recombination repair deficiency (HRD) score methodology using WES data and its application in patient-derived xenograft models
Authors: Jixin Wang, Krista Kinneer, Wenyan Zhong, Zhongwu Lai
Journal: Cancer Research (2023)

Abstract Homologous recombination repair deficiency (HRD) and mutations in genes involved with homologous recombination repair (HRR) are associated with sensitivity to platinum-based chemotherapy, topoisomerase 1 inhibitors and inhibitors targeting DNA repair pathway. Use of the Myriad HRD test for HRD determination in preclinical models is not feasible globally. To address this challenge, we developed an approach to generate HRD scores from whole exome sequencing (WES) data and applied it to assess HRD status in patient-derived xenograft (PDX) models. We used python package CNVkit for segmentation and gene-level/allele-specific copy number calling with customized settings according to CNVkit documentation. The reference was constructed using the WES BED file and hg38 reference genome when there are no paired control samples available. Next R package scarHRD was used to determine the HRD score that is the sum of loss of heterozygosity (LOH), telomere allele imbalances (TAI), and large fragment migrations (LST). The method was applied to the WES of 25 Xentech triple negative breast cancer (TNBC) PDX models to derive HRD scores. The samples were also separately profiled using Myriad’s MyChoice CDx assay. The two scores showed moderate correlation with Pearson r = 0.56. However, when n = 6 PDX models with low coverages (average depth &amp;lt;100x) were excluded, the Pearson r improved to r = 0.76. We also found that the absolute value of HRD score calculated by CNVkit/scarHRD is lower than that of Myriad HRD score. Furthermore, we evaluated the genomic landscape in this cohort of TNBC PDX models for the selected genes of HRR pathway (BRCA1, BRCA2, ATM, BRIP1, PALB2, RAD51C, BARD1, CDK12, CHEK1/2, FANCL, RAD51B, RAD51D, RAD54L). Sixteen models found to carry HRR mutations, with ATM and BRCA1 mutations being the most common ones, being found in 9 and 5 of 25 models, respectively. Although HRRm positive (HRRm+) models have higher HRD score for both Myriad HRD score and HRD score generated with CNVkit/scarHRD approach, the association between HRR (HRRm+/HRRm-) and Myriad HRD (HRD+/HRD- defined by HRD threshold of 42) is not statistically significant (Fisher’s exact test p value = 0.1998, odds ratio=3.5), likely due to small cohort sizes. These results suggest that combination of CNVkit and scarHRD for HRD score calculation may be an alternative approach for HRD identification in preclinical PDX models. Citation Format: Jixin Wang, Krista Kinneer, Wenyan Zhong, Zhongwu Lai. The development of homologous recombination repair deficiency (HRD) score methodology using WES data and its application in patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6553.
Abstract 6721: β3-adrenergic receptor correlates with tumor growth and progression in neuroblastoma
Authors: Alessia Boaretto, Gennaro Bruno, Nicoletta Nastasi, Claudio Favre, Maura Calvani
Journal: Cancer Research (2023)

Abstract Neuroblastoma (NB) is a heterogeneous, often aggressive, extracranial tumor and the most common malignancy to be diagnosed in the first year of life. It has been already demonstrated that the specific antagonism of the β3-adrenergic receptor (β3-AR) on NB tumor cells affects tumor growth. To confirm the results obtained with the pharmacological approach on the crucial role played by the β3-AR receptor in influencing different pro-tumoral signaling pathways, here we investigated the effect of CRISPR/Cas9-mediated knock-out of β3-AR gene (ADRB3) on human NB cell line BE(2)-C in vitro and in vivo. Inoculation of BE(2)-C β3-AR−/- cells in athymic nude mice (NU(N-Cr)-Foxn1nu) showed a strong reduction of NB tumor growth compared to wild type cells, and in some cases β3-AR knock-out tumor cells failed in producing a tumor mass. RNA Sequencing on these tumor masses showed alterations of signaling pathways related to various tumor mechanisms, such as proliferation, cell motility and cell differentiation. Furthermore, we evaluated by flow cytometry the expression of β3-AR in circulating tumor cells (CTCs) from NB patients with different degrees of disease. Following depletion with anti-CD45 magnetic beads, tumor cells were identified through the expression of specific tumor markers, CD56 and GD2. Results showed that a high expression of β3-AR correlates with poor prognosis, characterized by metastatic or recurrent tumors, compared to patients with a favorable clinical outcome that instead show a low expression of β3-AR. Overall, our results demonstrate the β3-AR involvement in supporting NB tumor growth and suggest a possible role in regulating the metastatic potential of this tumor. Citation Format: Alessia Boaretto, Gennaro Bruno, Nicoletta Nastasi, Claudio Favre, Maura Calvani. β3-adrenergic receptor correlates with tumor growth and progression in neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6721.